Development and Physiopathology of the digestive tract – DIGEST

Despite significant advances in the description of molecular controls of gut development in different animal models, little works have been done on the pathways involved during visceral smooth muscle cell differentiation. This differentiation is often affected in patients with congenital malformations of the gut. These malformations account for a significant percentage of all congenital defects, and the molecular descriptions of gut development would be beneficial in diagnostic and therapeutic treatment of these common human disorders. The present project focuses on the identification and the functional study of the molecular mechanisms that control the gut development and the visceral smooth muscle cell differentiation. We plan to use the chick embryo as animal model, and techniques from development (overexpressions of cDNAs in chick embryos, in situ hybridization, immunohistochemistry) and molecular biology (cloning, Microarray technology). In Aim 1, we aim to the function of the WNT signaling pathway during the development of the pyloric sphincter structure. What is the connection(s) between WNT pathway, SOX9 and BMP signaling pathway during the development and the differentiation of the pyloric sphincter? In Aim 2, we aim to study the function of candidate signaling pathways and transcription factors during the differentiation of the visceral smooth muscle cells in the stomach. Are the FGF signaling pathway, and Rho GTPase family members essential for the differentiation process? In Aim 3, we will examine the expression of the functionally essential factors and pathways in infantile hypertrophic pyloric stenosis, that present perturbations of the growth and differentiation of the pyloric sphincter and in gastrointestinal motility disorders (such as Intestinal Pseudo-obstruction syndrome and in Duchenne Muscular Dystrophy (DMD) patients). With this approach, we aim to identify the molecular mechanisms that control the differentiation of the visceral smooth muscle cells and also to better understand the etiology of different congenital diseases in order to understand the key trigger events of these pathologies. ...